Severe SARS-CoV-2 infection as a marker of undiagnosed cancer: a population-based study

No study has yet investigated if a severe SARS-CoV-2 infection represents a marker of an undiagnosed cancer. This population-based study, using the SNDS database, identified from 02/15/2020 to 08/31/2021, 41,302 individuals hospitalized in intensive care unit due to SARS-CoV-2 (ICU-gr) and 713,670 control individuals not hospitalized for SARS-CoV-2 (C-gr). Individuals were matched according to year of birth, sex and French department. The cancer incidence was compared in the two groups during the follow-up period (index date-12/31/2021), using Cox proportional hazards models adjusted on matching variables, socioeconomic characteristics and comorbidities. In the ICU-gr, 2.2% (n = 897) was diagnosed with a cancer in the following months, compared to 1.5% (n = 10,944) in the C-gr. The ICU-gr had a 1.31 higher risk of being diagnosed with a cancer following hospital discharge compared to the C-gr (aHR 1.31, 95% CI 1.22–1.41). A global similar trend was found when competing risk of death was taken into account (aHR 1.25, 95% CI 1.16–1.34). A significant higher risk was found concerning renal (aHR 3.16, 95% CI 2.33–4.27), hematological (aHR 2.54, 95% CI 2.07–3.12), colon (aHR 1.72, 95% CI 1.34–2.21), and lung (aHR 1.70, 95% CI 1.39–2.08) cancers. This suggests that a severe SARS-CoV-2 infection may represent a marker of an undiagnosed cancer.

Inclusion and exclusion criteria. We collected data on individuals aged ≥ 16 years, living in mainland France, having benefited from at least one health care reimbursement in the 2 years preceding the index date, with no history of cancer in the previous 5 years. Individuals living in nursing homes and twins < 22 years were excluded ( Fig. 1; Supplementary Table S1 online). Individuals were included in two groups, the ICU hospitalized group (ICU-gr) and the matched control group (C-gr). The two groups were matched on the basis of year of birth, sex, and French department (n = 95). Each individual from the ICU-gr was matched with between six (minimum) and 20 (maximum) individuals belonging to the C-gr (average number 17). We matched to a large number of controls (a maximum of 20 controls was deliberately chosen) in order to increase the representativeness of the C-gr when compared to the ICU-gr.
Sociodemographic characteristics and co-variables. The following sociodemographic characteristics were taken into account: age, sex, and region of residence. The social deprivation index was used as a measure of the socio-economic status. The following co-variables were analyzed: various comorbidities, addictive disorders, vaccination status for SARS-CoV-2, and immunosuppressive/oral corticoid treatment ( Table 1). The variables are defined in a previous article 2 , as the social deprivation index 22 . Outcome and censoring criteria. The outcome was the incidence of cancers in the two groups during the follow-up period. A cancer case was defined as any hospitalization for cancer or any long-term cancer-like condition needing health care reimbursement (including in situ cancers). The censoring criteria which required the exclusion of the individual (or the end of the follow-up) after the initial inclusion were the death of the individual (ICU-gr and C-gr), the outcome occurrence (ICU-gr and C-gr), and the hospitalization due to a SARS-CoV-2 infection (C-gr; 5177 control individuals in the C-gr, i.e. < 1%, were censored because they were hospitalized for a SARS-CoV-2 infection; 694 of these control individuals were then re-included in the ICU-gr). The censoring criteria were applied at the individual level and censoring was done at the first event that occurred. The death was recorded through death certificates registered in the database, which therefore included deaths from any cause. Statistical analysis. The categorical variables are reported as frequencies with percentages and the continuous variables reported as means with standard deviations. To study the association between severe SARS-CoV-2 infection and overall cancer, as well as the association with specific cancer sites, we conducted Cox proportional hazards models that were systematically adjusted on matching variables and with further adjustment for all the co-variables previously described. In secondary analyses, we excluded in situ cancers, lung cancers or events occurring during the SARS-CoV-2 hospital stay. The follow-up was also divided into two sub-periods, distinguishing the first 3 months from the rest of the period, to assess the consistency of the associations over time (Table 3). Analyses by sex and age groups were performed (Table 4). Analysis taking into account death as competing event was conducted using Cox cause-specific hazard method (Supplementary Table S5 online). Missing data in the database, which concerned only the social deprivation index, were analyzed as a separate group (small number of missing data: 1.8% in C-gr, 1.6% in ICU-gr). All statistical analyses were performed using SAS software, version 9.4 (SAS Institute Inc.).

Results
Between February 15, 2020, and August 31, 2021, 41,302 individuals were hospitalized in the ICU in France due to a SARS-CoV-2 infection. These individuals were matched with 713,670 individuals who were not hospitalized for a SARS-CoV-2 infection (Fig. 1).   www.nature.com/scientificreports/ 3.8%; C-gr 5.0%). The majority of individuals of the two groups were not vaccinated against SARS-Cov-2 (without any vaccination dose received at the index date), even if unvaccinated individuals were more prevalent in the ICU-gr (ICU-gr 95.3%; C-gr 86.5%). Only 0.8% of individuals in the ICU-gr (n = 324) and 6.6% of individuals in the C-gr (n = 47,100) had received at least two doses of vaccine against SARS-CoV-2 at that time. However, SARS-CoV-2 vaccines were available to the French population only since December 27, 2020. More than twice as many individuals in the ICU-gr were under immunosuppressive therapy compared to the C-gr (ICU-gr 2.4%; C-gr 0.9%) and more individuals of the ICU-gr were under oral corticoid treatment (which includes any oral dose) compared to the C-gr (ICU-gr 3.1%; C-gr 0.7%). Individuals in the ICU-gr had more comorbidities overall compared to individuals in the C-gr. The median follow-up period was 327 days for the ICU-gr (interquartile range (IQR) 257-444 days) and 340 days for the C-gr (IQR 267-457 days).
Cancer incidence in the two groups. In Table 2). The association obtained between the outcome and the exposure is relatively stable (same order of magnitude) between univariable and multivariable models, as is the range of the 95% confidence interval ( Stratification according to age and sex. The association between exposure and the risk of cancer was stronger in women compared to men (aHR 1.69, 95% CI 1.48-1.93, and aHR 1.20, 95% CI 1.10-1.30, respectively) and among individuals younger than 60 years old compared to older individuals (aHR 1.78, 95% CI 1.52-2.09, and aHR 1.22, 95% CI 1.12-1.32, respectively). The strongest association was found in women under 60 years old (aHR 2.15, 95% CI 1.65-2.80) ( Table 4).

Discussion
This large population-based study included 41,302 individuals hospitalized in ICU due to SARS-CoV-2 infection (between February 15, 2020 and August 31, 2021) and 713,670 control individuals. Among these individuals, 2.2% of the ICU-gr was diagnosed with a cancer compared to 1.5% in the C-gr. Individuals in the ICU-gr had a 1.31 higher risk of being diagnosed with a cancer compared to the C-gr. The association was stronger by limiting the follow-up period to the first 3 months, and among women. The ICU-gr had a significant higher risk of being diagnosed with a renal, hematological, colon, or a lung cancer, compared to the C-gr. No significant differences were found for the other sites of cancers.
To the best of our knowledge, to date no studies have been conducted on this issue. However, studies with similar design aiming to assess the risk of cancer following other diseases, such as herpes zoster, have already been conducted. For example, a study conducted in the United Kingdom, using the General Practice Research Database (including 74,029 individuals), demonstrated the link between individuals having had herpes zoster and the risk of them being diagnosed with cancer in the following years 26  www.nature.com/scientificreports/ This study cannot conclude on a causal effect of a severe SARS-COV-2 infection on the risk of developing a cancer in the following months. Cancer screening and diagnosis may indeed have been different between the two groups, leading to a detection bias. Individuals hospitalized in the ICU-gr may have benefited from more lung scans, used as a screening tool for lung cancers, and from more repetitive blood tests that allowed screening of hematological diseases. On the other hand, screening by PSA or mammography may have been less frequent during the ICU stay or at discharge, as this was not necessarily a priority for these patients. For the control group, individuals were probably able to benefit from a better screening for certain cancers as they did not experience serious health events and were in better health condition to receive these screenings. However, since individuals hospitalized in ICU for a SARS-CoV-2 infection had a 31% higher risk of being diagnosed with a cancer in an average of 168 days following the index date, a severe SARS-CoV-2 infection may represent a marker of an underlying undiagnosed cancer, especially as the association with the risk of being diagnosed with a cancer was stronger in the first 3 months following hospitalization. Therefore, a more systematic screening could be more efficient during this period of time. It should also be noted that identical multivariate analyses were performed taking into account follow-up starting only from hospital discharge. These additional results showed a 17% increased risk of being diagnosed with a cancer in the ICU-gr compared to the C-gr, which underlines the fact that even when the follow-up does not include the hospitalization period, a similar trend is confirmed despite the possible detection bias previously described. Furthermore, multivariate analyses were performed taking into account the competing risk of death, highlighting a global similar trend with a 25% increased risk of being diagnosed with a cancer in the ICU-gr compared to the C-gr.
Regarding cancer sites, renal, hematological, colon and lung cancers were most likely to be diagnosed following a severe SARS-CoV-2 infection. While it may be more intuitive to understand why some type of hematological cancer might impact the immune system, it may be more difficult to understand the link between renal or colon cancer and higher frailty to SARS-Cov-2 infection. Nevertheless, some recent studies have already confirmed the immune dysfunction associated with renal and colon cancers [27][28][29] , as well as the fact that any type of cancer may promote immune dysfunction 30 . This could represent one explanation to our findings.
Strengths of the study. The main strength of this study is that the SNDS is a claims database that allowed us to analyze the risk of being diagnosed with a cancer from the comprehensive population without cancer history, thus limiting selection bias. Furthermore, a large number of individuals were included in the study, as the database includes the whole French population. In addition, all analyses were adjusted with a multivariable model to minimize confounding factors.  www.nature.com/scientificreports/ infection was limited to individuals hospitalized in ICU. However, this allowed us to focus on the most severe cases of SARS-CoV-2 infections. Secondly, information was potentially wrongly classified for certain variables (obesity, tobacco dependence, alcohol related disorders), which are significantly underestimated in this database. For instance, it is possible that some patients who smoke were misclassified as non-smokers in the database, thus underestimating this variable. However, this should not substantially modify the association between the risk of being diagnosed with a cancer and the group of exposure, except probably for obesity. Thirdly, we did not have information on the medication of residents in nursing homes, which have their own pharmacy, and therefore did not identify their comorbidities exhaustively. For this reason and knowing that many of these patients were not admitted to hospital during the first wave of SARS-CoV-2 pandemic because of the hospital restrictions in place at this time in France, we excluded this subpopulation. Finally, our study may also have been affected by residual confounding factors due to differences between the two groups, although matching and adjustment for a high range of comorbidities have been done.

Conclusion
In conclusion, this study is the first to suggest an association between severe SARS-CoV-2 infection and cancer diagnosis in the following months, suggesting that a severe SARS-CoV-2 infection may represent a marker of undiagnosed cancer. More research is needed to determine the nature of the relationship between an underlying cancer and a severe SARS-CoV-2 infection. Based on this future research, it would be necessary to discuss whether more targeted screening should be offered or not to this population of individuals.

Data availability
The data that support the findings of this study are available from the French Data Protection Office (CNIL Commission Nationale de l'Informatique et des Libertes) via the French Health Data Hub (https:// www. snds. gouv. fr/ SNDS/ Proce ssus-d-acces-aux-donne es and https:// www. health-data-hub. fr/) but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of the French Data Protection Office (CNIL Commission Nationale de l'Informatique et des Libertes). All methods were carried out in accordance with relevant guidelines and regulations. All experimental protocols were approved by a named institutional and/or licensing committee, as detailed in the paragraph below: EPI-PHARE has permanent regulatory access to the data from the French National